Method for determining the blood flow in a coronary artery

ABSTRACT

The invention relates to a method and a system for determining the blood flow in an individual coronary artery of a patient, wherein the method comprises the steps of positioning a temperature sensor mounted at a distal portion of a guide wire at a distal position in the coronary artery, positioning an infusion catheter in the coronary artery such that the distal end of the infusion catheter is proximally of the temperature sensor, measuring the blood temperature with the temperature sensor, infusing cold indicator fluid with a known infusion rate and known or measurable temperature into the coronary artery by the infusion catheter, measuring the temperature of the mixture of blood and indicator fluid by the temperature sensor, and calculating the coronary blood flow by a formula based on the known and measured quantities. In an extended version, the method comprises steps for relating the calculated coronary flow value to related normal flow values, or related FFR values, or a related flow resistance.

FIELD OF THE INVENTION

The present invention relates generally to in vivo measurements of bloodflow in vessels, and in particular to blood flow measurements inindividual coronary arteries by means of a temperature sensitive sensormounted on a guide wire and application of the thermodilution principlewith continuous infusion of an indicator fluid.

BACKGROUND OF THE INVENTION

From the literature (e.g. Ganz et. al., “Measurement of coronary sinusblood flow by continuous thermodilution in man”, Circulation 44:181-195,1971) it is known that the thermodilution principle can be utilized forin vivo measurements of blood flow in the coronary sinus of humanbeings. These measurements involve the introduction of a speciallydesigned catheter into the coronary sinus of a patient and injection ofa cold indicator fluid from an injection orifice close to the cathetertip. The indicator fluid was flowing along the shaft of the catheter andcaused a temperature drop in the blood temperature that was registeredby several thermistors coupled in a Wheatstone-bridge arrangement. Byknowledge of the indicator temperature and injection rate as well as themeasured temperature drop caused by the injected indicator fluid, thecoronary sinus flow can be estimated. This type of catheter, with itscomparatively large outer diameter, can, however, not be used formeasurements of blood flow in individual coronary arteries, and themethod suffered also from a rather large variability within themeasurements.

The U.S. Pat. No. 6,754,608, which is assigned to the present assignee,reveals that a temperature sensitive sensor mounted at a distal portionof a guide wire could be used for continuously monitoring of thetemperature of blood passing the sensor. In use, a guide catheter isintroduced to a proximal portion of an artery, and then the sensor guidewire is introduced into the guide catheter and is advanced until thesensor is located downstream of the catheter tip. When cold salineinjected into the artery from the open catheter tip passes thetemperature sensitive sensor, the sensor will register a temperaturedrop which is a function of blood flow. This patent is, however,directed to a system for measurements of coronary flow reserve (CFR),wherein a known amount of saline is injected as a bolus, and no suitablemeasures are taken to adapt the system to measurements of blood flow bycontinuous thermodilution. A special infusion catheter is, for example,not disclosed. It can further be noted that in the CFR proceduredisclosed in U.S. Pat. No. 6,754,608, the temperature is not measuredand presented as an absolute value, but instead the temperature droptriggers the start of a time measurement.

SUMMARY OF THE INVENTION

A first object of the present invention is therefore to provide a methodfor measuring coronary blood flow in individual coronary arteries byapplication of the thermodilution principle with continuous infusion ofan indicator fluid. The invention also provides a system for carryingout the method.

For a specific patient and a specific medical situation it may be veryvaluable to obtain coronary blood flow as an absolute number, but it isalso known that the coronary flow varies significantly between differentindividuals; and moreover the coronary flow of a patient who suffersfrom a coronary disease will change with the development of the disease,and the flow is also dependent on other individual and temporary medicalcircumstances. In other words, many times absolute values of coronaryflow have a rather limited medical significance.

A second object of the present invention is therefore to provide amethod for enhancing the medical usefulness of blood flow measurements,and in particular to provide a method with which absolute values ofblood flow measured through application of the continuous thermodilutionprinciple in a patient who suffers from a coronary disease can berelated to normal blood flow values for this particular patient. Theinvention also provides a system for carrying out the method.

To achieve the object of providing a method for measuring coronary bloodflow, the present invention provides a method comprising the followingsteps: positioning of a guide wire mounted temperature sensor at adistal position in a coronary artery of a patient, positioning of aninfusion catheter in the coronary artery such that the distal end of theinfusion catheter is located proximally (upstream) of the temperaturesensor, measurement of blood temperature by the temperature sensor,continuous infusion of an indicator fluid (e.g. saline) with a knowninfusion rate and with known or measurable temperature through theinfusion catheter, measurement of the temperature of the mixture ofblood and indicator fluid by the temperature sensor, and calculation ofabsolute coronary flow according to a formula based on the known andmeasured quantities.

The above method comprises further preferably the induction of steadystate hyperaemia in the patient, such that the obtained absolutecoronary flow is the maximum absolute coronary flow. In a preferredembodiment of the invention, the temperature of the indicator fluid ismeasured by the same guide wire mounted temperature sensor as is usedfor measurements of blood and mixture temperatures. The positioning ofthe sensor guide wire and infusion catheter is usually accomplishedthrough a guide catheter that has been inserted into the patient'saorta, and the method can be supplemented with a corresponding step.

To achieve the object of enhancing the medical usefulness of coronaryblood flow measurements, the present invention also provides an extendedversion of the method, which comprises the following steps: positioningof a guide wire mounted temperature sensor at a distal position in acoronary artery of a patient, positioning of an infusion catheter in thecoronary artery such that the distal end of the infusion catheter islocated proximally (upstream) of the temperature sensor, induction ofsteady state hyperaemia in the patient, measurement of blood temperatureby the temperature sensor, continuous infusion of an indicator fluid(e.g. saline) with a known infusion rate and with known or measurabletemperature through the infusion catheter, measurement of thetemperature of the mixture of blood and indicator fluid by thetemperature sensor, calculation of maximum absolute coronary flowaccording to a formula based on the known and measured quantities,measurement of the hyperaemic aortic pressure, positioning of a guidewire mounted pressure sensor at a distal position in the coronary arteryand measurement of a distal coronary pressure, calculation of a FFR(Fractional Flow Reserve) value as a ratio of the measured hyperaemicaortic pressure and the measured distal coronary pressure, andcalculation of a related FFR value and/or calculation of a relatednormal maximal flow value according to formulas based on the known,measured and calculated quantities.

In preferred embodiments of the invention, the sensor guide wire as wellas the infusion catheter is introduced into the coronary artery via aguide catheter inserted into the patient's aorta, and the hyperaemicaortic pressure is measured by a pressure transducer connected to theguide catheter. In another preferred embodiment, the distal coronarypressure and the blood temperature are measured with the same guide wiremounted sensor, i.e. the sensor is a temperature sensitive as well aspressure sensitive sensor. Optionally, the method can further includethe following steps: positioning of a balloon arranged on a catheter inthe coronary artery such that the balloon is positioned proximally(upstream) of the guide wire mounted pressure sensor, inflation of theballoon to create total occlusion of the coronary artery, andmeasurement of the coronary wedge pressure by the pressure sensor. Theballoon is then deflated, and—like in the previous method—thetemperature of the indicator fluid can preferably be measured by thesame guide wire mounted temperature sensor as is used for measurementsof blood and mixture temperatures. As will be discussed below, themethod can, if needed, further be supplemented by a measurement of thevenous pressure, which can be done through a multipurpose catheterplaced in the right atrium of the patient's heart. Since all relevantperfusion pressures are measured and all relevant flows can becalculated, the method can further be supplemented with calculations ofthe myocardial, coronary and collateral resistances.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a model that schematically illustrates thethermodilution principle with continuous infusion of indicator fluid.

FIG. 2 illustrates schematically a model representing the coronarycirculation.

FIG. 3 is a schematic illustration of a coronary artery in which a guidecatheter, an infusion catheter, and a guide wire mounted sensor havebeen positioned in order to perform the steps included in the methodaccording to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before describing the method according to the invention in detail, thetheoretical framework on which the methods are based will be brieflypresented. How the different parameters actually are obtained will bethoroughly explained below.

With reference to FIG. 1, the absolute flow in a coronary artery of apatient, who is in a state of hyperaemia, can according to the presentinvention be calculated from the following equation $\begin{matrix}{Q_{b} = {Q_{k}\frac{T_{k} - T_{b}}{T - T_{b}}}} & {{Eq}.\quad\left( {1a} \right)}\end{matrix}$where Q_(b) is the absolute coronary artery flow, Q_(k) is the infusionrate of the indicator fluid, T_(k) is the temperature of the indicatorfluid, T_(b) is the blood temperature, and T is the temperature of themixture of blood and indicator fluid. When the patient during themeasurement is in hyperaemia, Q_(b) will consequently be the maximumabsolute coronary artery flow. The equation above is based on someassumptions and approximations, e.g. that the differences in density andspecific heat of blood and indicator fluid, respectively, can beneglected, that complete mixing occurs between blood and indicatorfluid, and that heat transfer to surrounding tissues is insignificant.It should also be noted that Eq. (1a) differs from the correspondingequation given in the above-referenced article by Ganz et. al. in thatEq. (1a) correctly presumes that injection of an indicator fluid leadsto a decrease in the incoming blood flow in the coronary artery. Whenthe infusion rate Q_(k) of the indicator fluid is known and thetemperature T_(k) of the indicator fluid is known or measured, Eq. (1a)can, when the blood temperature T_(b) before infusion of indicator fluidand the mixing temperature T after infusion of indicator fluid have beenmeasured, be employed to calculate the absolute coronary flow Q_(b). Itcan be noted that from a strict scientific point of view, it is not theinfused fluid itself that is an indicator; rather it is the temperature(cold) of the infused fluid that is the indicator. However, as iscustomary within the field, the infused fluid (e.g. saline) will bereferred to as the indicator fluid.

As mentioned above, Eq. (1a) is applicable in a situation where apatient is set in a state of hyperaemia such that the incoming bloodflow can not be increased. If, on the other hand, the incoming bloodflow can be increased, i.e. when the patient is not in hyperaemia, thefollowing equation can be used $\begin{matrix}{Q_{b} = {Q_{k}\frac{T - T_{k}}{T_{b} - T}}} & {{Eq}.\quad\left( {1b} \right)}\end{matrix}$

A calculation of maximum absolute coronary flow according to Eq. (1a) orEq. (1b), where the included parameters have been obtained bytemperature measurements in a patient who suffers from a coronarydisease, will give the coronary flow at the patient's present state. Fora specific patient and a specific medical situation it may be veryvaluable to obtain coronary blood flow as an absolute number, but manytimes such absolute numbers have a rather limited medical significance.Reasons for this are, for example, that for an individual patient theamount of myocardium to be perfused by a given coronary artery is notknown and this amount of myocardium can also change over time. Further,a decreased blood flow can either mean a coronary stenosis or amicrovascular disease, or a combination of both, i.e. a measureddecrease in blood flow does not discriminate between these two factors.Furthermore, the coronary blood flow varies considerably betweendifferent individuals and arteries, and is also dependent on bloodpressure. For a given patient suffering from a coronary disease, ameasured value of maximum coronary blood flow can therefore not becompared with any “normal” value. If, for example, the patient suffersfrom a coronary stenosis, a measured flow value does not say much aboutthe normal flow that would prevail if the patient were cured from thisstenosis. Herein, the term “normal” is used to indicate the flow thatwould prevail in a healthy patient, e.g. when the patient is free fromstenosis. It should in particular be noted that the term “normal”—unlessotherwise explicitly stated—refers to the normal values for a specificpatient, and not to, for example, some average values for a group ofindividuals. As was stated above, the present invention provides amethod with which the measured flow in a patient suffering from acoronary disease can be related to normal flow values for thisparticular patient, i.e. the flow values that would prevail if thepatient were cured from his or her disease. According to the inventionthis is accomplished through the concept of fractional flow reserve(FFR).

The concept of fractional flow reserve (FFR) is thoroughly explained inseveral medical articles. Herein special reference is made to the book“Coronary Pressure” by N. H. J. Pijls and B. De Bruyne, 2nd edition,Kluwer Academic Publishers, The Netherlands, 2000. Below only the mostrelevant relations will be presented; however, the entire contents ofthis book (including the description of various techniques andequipment) is incorporated herein by reference.

The coronary circuitry is schematically illustrated in FIG. 2, where AOdenotes the aorta and RA the right atrium, and P_(a) represents arterialpressure in the aorta, P_(d) distal coronary pressure, P_(v) venouspressure, Q blood flow through the myocardial vascular bed, Q_(c)collateral flow, Q_(s) blood flow through the supplying epicardialcoronary artery, R resistance of the myocardial vascular bed, R_(c)resistance of the collateral circulation, and R_(s) denotes theresistance of a stenosis in the supplying epicardial coronary artery. Attotal occlusion of the coronary artery, which can be artificiallyinduced by inflating a balloon arranged at a catheter, the distalcoronary pressure P_(d) is called coronary wedge pressure and is denotedby P_(w).

Now, the myocardial fractional flow reserve FFR_(myo) is defined as thefraction of maximum flow that still can be maintained in spite of thepresence of a stenosis, i.e. FFR_(myo) indicates to what extent apatient is limited by his or her coronary artery disease, andconsequently FFR_(myo) is given by $\begin{matrix}{{FFR}_{myo} = {\frac{\begin{matrix}{{Maximum}\quad{myocardial}\quad{flow}\quad{in}} \\{{the}\quad{presence}\quad{of}\quad a\quad{stenosis}}\end{matrix}\quad}{{Normal}\quad{maximum}\quad{myocardial}\quad{flow}} = \frac{Q}{Q^{N}}}} & {{Eq}.\quad(2)}\end{matrix}$where the superscript N indicates the normal value of the respectivequantity, and therefore, by definition, Q^(N)=Q_(s) ^(N) and Q_(c)^(N)=0. In analogy to myocardial fractional flow reserve, coronaryfractional flow reserve FFR_(cor) can be defined as maximum coronaryartery blood flow in the presence of a stenosis divided by normalmaximum coronary artery flow. Thus, $\begin{matrix}{{FFR}_{cor} = {\frac{\begin{matrix}{{Maximum}\quad{coronary}\quad{flow}\quad{in}} \\{{the}\quad{presence}\quad{of}\quad a\quad{stenosis}}\end{matrix}\quad}{{Normal}\quad{maximum}\quad{coronary}\quad{flow}} = \frac{Q_{S}}{Q_{S}^{N}}}} & {{Eq}\quad.\quad(3)}\end{matrix}$

The ratio of collateral blood flow to normal maximum myocardial flow isconsequently written as Q_(c)/Q^(N) and is called fractional collateralflow; and the quantity (Q_(c)/Q^(N))_(max) is the maximum recruitablecollateral flow as may be encountered during coronary artery occlusion.

All these quantities, FFR_(myo), FFR_(cor), Q_(c)/Q^(N) and(Q_(c)/Q^(N))_(max), can be obtained by measuring the differentpressures in the coronary circuitry, and are given by $\begin{matrix}{\left( {Q_{c}/Q^{N}} \right)_{\max} = {\frac{P_{w} - P_{v}}{P_{a} - P_{v}} = {{const}.}}} & {{Eq}.\quad(4)} \\{{FFR}_{cor} = \frac{P_{d} - P_{w}}{P_{a} - P_{w}}} & {{Eq}.\quad(5)} \\{{FFR}_{myo} = \frac{P_{d} - P_{v}}{P_{a} - P_{v}}} & {{Eq}.\quad(6)} \\{\left( {Q_{c}/Q^{N}} \right) = {{FFR}_{myo} - {FFR}_{cor}}} & {{Eq}.\quad(7)}\end{matrix}$

Here, Eq. (4) states the fundamental observation that(Q_(c)/Q^(N))_(max) is constant under conditions of maximumvasodilation. By definition P_(w) can only be measured at coronaryocclusion, and Eq. (4) can therefore be used to calculate P_(w) as itwould be at other P_(a) during non-occluded states, e.g. before andafter a percutaneous transluminal coronary angioplasty (PTCA) procedure.

From the above, it should now be clear that when the maximum coronaryflow Q_(s) has been measured in a patient suffering from a stenosis, andwhen the relevant pressures, i.e. P_(d), P_(w) and P_(a), have beenobtained for this particular patient such that FFR_(cor) can becalculated through Eq. (5), then Eq. (3) can be used to calculate thenormal maximum coronary flow Q_(s) ^(N) that this patient would have ifhe or she were cured from the stenosis. It should further be clear that,with knowledge of also the venous pressure P_(v) and application of Eqs.(6) and (2), the maximum myocardial flow Q in the presence of a stenosiscan be calculated. The collateral flow Q_(c) can simultaneously becalculated as Q_(c)=Q−Q_(s), and the fractional collateral flow can becalculated from Eq. (7). In fact, the concept of FFR gives the relationbetween myocardial, coronary and collateral flow both before and after amedical operation (e.g. PTCA) that removes a stenosis. If one of theseparameters is calculated quantitatively, all the others are known aswell.

From FIG. 2 it follows further that when a flow, such as the coronaryartery flow, has been measured together with the relevant perfusionpressures, the different resistances R, R_(s) and R_(c) can becalculated. The resistance R_(s) of a stenotic artery can, for example,be calculated as $\begin{matrix}{R_{s} = \frac{P_{a} - P_{d}}{Q_{s}}} & {{Eq}.\quad(8)}\end{matrix}$

At total occlusion, i.e. R_(s)=∞ and Q_(s)=0 such that Q=Q_(c) andP_(d)=P_(w), the myocardial resistance R can be calculated according to$\begin{matrix}{R = \frac{P_{w} - P_{v}}{Q}} & {{Eq}.\quad(9)}\end{matrix}$while the collateral resistance R_(c) can be obtained from$\begin{matrix}{R_{c} = \frac{P_{a} - P_{w}}{Q}} & {{Eq}.\quad(10)}\end{matrix}$

Having established the theoretical basis for the present invention, thepractical details of a medical procedure for measuring blood flow in anindividual coronary by application of the thermodilution principle withcontinuous infusion of an indicator fluid are now to be described. Asalready has been mentioned, the temperature as well as the pressuremeasurements are performed with a guide wire mounted sensor. Although itis within the scope of the present invention that the pressuremeasurements are executed by a specially dedicated pressure sensitivesensor, whereas the temperature measurements are executed with aseparate, specially dedicated temperature sensitive sensor, both thepressure measurements and the temperature measurements are preferablyaccomplished with the same guide wire mounted sensor. A suitable guidewire mounted sensor is, for example, manufactured and sold by theSwedish company Radi Medical Systems AB under the registered trademarkPressureWire® Sensor, and is inter alia described in the U.S. Pat. No.6,343,514 and Re 35,648, which are assigned to the present assignee. Thesensor signals representing the measured pressures and temperatures areadvantageously processed in a specially dedicated device for monitoring,calculating and displaying the measured variables. Such a device is soldunder the registered trademark RadiAnalyzer® by Radi Medical Systems AB,and is described in the U.S. Pat. No. 6,565,514, which is assigned tothe present assignee. The entire contents of both '514 patents and the'648 patent (including the description of various techniques andequipment) is incorporated herein by reference.

When access to the artery of a patient has been obtained, the methodaccording to the present invention usually commences with theintroduction of a guide catheter into the patient's aorta, as iswell-known in the field. If needed, a conventional guide wire can beemployed to facilitate the introduction of the guide catheter, as alsois well-known in the field. A guide wire mounted sensor is subsequentlyintroduced into the guide catheter, and is then advanced out of the endof the guide catheter and into a specific coronary artery until thetemperature sensor is located at a distal position in the coronaryartery. A specially designed infusion catheter is then threaded onto thesensor guide wire, and is advanced along the sensor guide wire until theend of the infusion catheter is outside the end of the guide catheterand is located proximally (upstream) of the temperature sensor in thespecific coronary artery. As an alternative, a conventional guide wirecould be used to locate the specific coronary artery of interest, andthe infusion catheter can thereafter be threaded over this conventionalguide wire, which in a separate subsequent step is replaced by thesensor guide wire. It is even conceivable, and within the scope of thepresent invention, to position the infusion catheter in an individualcoronary artery without any guidance by a guide wire. Furthermore,although a guide catheter usually is used in coronary interventions, itis not an absolute necessity for practising the present invention, andthe invention, as defined by the claims, comprises embodiments wherein aguide catheter has been dispensed with. In such a case, a guide wire,with or without a sensor mounted thereon, an infusion catheter, or acombination of both, is utilized to locate a specific coronary arterywithout the assistance of a guide catheter; or a guide catheter could beremoved before the temperature measurements commence.

Practical experiments have shown that a special infusion catheter isusually needed to achieve adequate mixing of blood and indicator fluid.As will be described below, in a preferred embodiment of the invention,the temperature of the indicator fluid is measured at the outlet of theinfusion catheter such that any loss of heat through the infusioncatheter mantle has no affect on the measurements. If, however, thetemperature of the indicator fluid is measured more proximally of thedistal tip, the infusion catheter should be designed to reduce loss ofheat through the catheter mantle to a minimum. To ensure complete, or atleast sufficient, mixing of indicator fluid and blood, a 2-3 F infusioncatheter can be used. The infusion catheter should have a sufficientnumber of side holes provided along a distal portion thereof, the lengthof which can be in the order of 1-3 cm. Suitable infusion catheters are,for example, obtainable from the medical technology companies BostonScientific or OCCAM. It should further be noted that the present methodpromotes complete mixing of blood and indicator fluid in that theindicator fluid flows away from the infusion catheter, rather than alongthe infusion catheter—as in the previously suggested method by Ganz et.al.

With a guide wire, a distal portion of which is provided with atemperature sensitive sensor, in place in a specific coronary artery, aninfusion catheter is positioned over the sensor guide wire, and isadvanced to a position proximally of the temperature sensor. As analternative, the infusion catheter could first be positioned in acoronary artery (presumably by assistance of a conventional guide wire),and the sensor guide wire is then introduced into the infusion catheter,and is advanced out of the end of the infusion catheter to a distalposition in the artery. The distance between the sensor and the infusioncatheter end ranges from about 1 cm to 15 cm, preferably 3-6 cm, theimportant consideration being that complete mixing takes place betweenblood and indicator fluid. From the above it should be understood thatthe order of the first positioning steps is not crucial for practisingthe method; and the invention, as defined in the claims, encompasses allways of inserting and positioning an infusion catheter and a sensorguide wire in a coronary artery. If a guide catheter is used, also thiscan be positioned in any suitable way without departing from the scopeof the present invention. FIG. 3 illustrates schematically therespective locations of a guide catheter, an infusion catheter and aguide wire mounted sensor in a coronary artery.

With an infusion catheter and a temperature sensor correctly positionedin a coronary artery, the next step in the present method is to measurethe blood temperature. This is accomplished by the temperature sensitivesensor arranged at the distal portion of the sensor guide wire. Anexample of a suitable sensor comprises a support body provided with adiaphragm covering a cavity formed in the support body. A pressuresensitive element is mounted on the diaphragm and a temperaturesensitive resistor (or other component) with known temperaturedependence is mounted in the vicinity of the pressure sensitive element.With this arrangement, which is disclosed in the above-mentioned U.S.Pat. No. 6,343,514, the output signal from the sensor is dependent onthe temperature of the medium (i.e. blood) surrounding the sensor, andfrom the known temperature dependence the output signals can beconverted to the temperature of the surrounding medium. The latter can,for example, be done in the device disclosed in the above-referencedU.S. Pat. No. 6,565,514. The output signals from this particular sensorare also dependent on the ambient pressure, and the sensor can therebypreferably be used to also measure the relevant blood pressures. It is,however, within the scope of the present invention to use other types ofguide wire mounted sensors, as long as the outer diameter of the sensorguide is small enough to allow introduction into individual coronaryarteries such that selective coronary artery flow can be measured.

When the blood temperature has been measured, cold indicator fluid, e.g.saline with a temperature well below the blood temperature, is injectedinto the infusion catheter and is further infused into the coronaryartery. The indicator fluid mixes with the blood and causes atemperature drop, which is registered by the sensor. The indicator fluidis preferably stored in a thermally isolated reservoir, and is therefromby a suitable device, such as a pump, delivered at a constant and knowninfusion rate. Clearly, the magnitude of the decrease in temperature atthe measurement site will be a function of blood flow and temperature ofindicator fluid; and with knowledge of these parameters, the absolutecoronary flow in this particular artery can be calculated by applicationof Eqs. (1a) or (1b) above.

The temperature of the indicator fluid is preferably measured at theexit of the infusion catheter by the same guide wire mounted sensor asis used for the blood temperature measurements. This is accomplished bysimply retracting the sensor guide wire until the sensor is locatedinside the infusion catheter and close to the distal exit opening of theinfusion catheter. Advantageously, the temperature of the mixture ofblood and indicator fluid is recorded during the retraction of thesensor guide wire, to thereby detect any inconsistencies orirregularities in the mixture temperature, which could arise due toincomplete mixing or other undesired flow phenomena. As an alternative,the temperature of the indicator fluid could be measured with some otherdevice, such as a thermometer, e.g. at a position more proximally of theinfusion catheter tip. The measurement of the indicator temperaturecould alternatively be performed before the mixing temperature ismeasured. It is also possible to perform the measurement of the bloodtemperature after the measurements of indicator and mixing temperatures.

The previously described method steps have provided the parametersnecessary for calculating the blood flow prevailing in the coronaryartery where the infusion catheter and sensor have been located, and,more specifically, for calculating the blood flow at the injection pointof the indicator fluid. The measured parameters, i.e. the bloodtemperature T_(b), the indicator fluid temperature T_(k) and the mixturetemperature T, together with the known infusion rate Q_(k), can now beinserted into Eqs. (1a) or (1b) to thereby calculate the absolutecoronary blood flow Q_(b). Although it is not an indispensableprerequisite for the application of the thermodilution principle, apatient will normally be brought in a state of hyperaemia before themeasurements take place. The flow calculated through Eq. (1a) will thenbe the maximum absolute coronary flow.

If the steps of the above method are conducted in a patient sufferingfrom a flow restricting disease, such as a stenosis, the measuredcoronary flow will apparently be the momentary flow, which consequentlydepends on the present state of the stenosis. To be able to relate themeasured flow to a normal flow for this particular patient, and tothereby enhance the medical usefulness of the flow measurement, theabove method can be supplemented with further measurements using FFR. Itis further possible to relate the measured maximum coronary flow toother flows, such as maximum myocardial flow or maximum collateral flow,or to different resistances prevailing in the coronary circuitry.

A measured blood flow in a stenotic artery is related to a normal,unstenotic flow value through the concept of fractional flow reserve(FFR), as is shown in Eqs. (2) and (3) above with reference to FIG. 2.For example, by dividing the maximum coronary flow Q_(s) measuredaccording to the method described above with the coronary fractionalflow reserve FFR_(cor), the normal (unstenotic) maximum coronary flowQ_(s) ^(N) is obtained for this particular coronary artery. Further, ifthe maximum myocardial flow Q in the presence of a stenosis is wanted,the measured coronary flow Q_(s) is multiplied with FFR_(myo)/FFR_(cor).In fact, it follows from Eqs. (2) to (7) that if one flow value isknown, all the other flows, i.e. myocardial, coronary and collateralflows, can be calculated both with as well as without the presence of astenosis.

A closer examination of Eqs. (4), (5) and (6) reveals that FFR_(cor),FFR_(myo) and (Q_(c)/Q^(N))_(max) can be obtained by measuring therelevant perfusion pressures. If, for example, the pressure P_(d)distally of a stenosis, the aortic pressure P_(a) proximally of thestenosis and the venous pressure P_(v) all are measured, then themyocardial fractional flow reserve FFR_(myo) can be calculated accordingto Eq. (6); and if total occlusion is created in the artery such thatP_(v) becomes the wedge pressure P_(w), then FFR_(cor) can be calculatedfrom Eq. (5), while (Q_(c)/Q^(N))_(max) can be calculated from Eq. (4).

According to embodiments of the invention, the distal pressure P_(d)(and, at total occlusion, the wedge pressure P_(w)) is measured with aguide wire mounted pressure sensor. In a preferred embodiment of theinvention, this pressure sensor is the same sensor that is used for thepreviously described temperature measurements. Thus, the sensor is atemperature sensitive as well as pressure sensitive sensor. It is,however, also conceivable to use other types of guide wire mountedsensors, e.g. a temperature sensitive sensor could be used for thetemperature measurements, while another, pressure sensitive sensor isused for the pressure measurements. The aortic pressure P_(a) could bemeasured with a guide wire mounted sensor, e.g. the same sensor that isused for pressure measurements in a specific coronary artery, but aperhaps more common procedure would be to measure the aortic pressureP_(a) with a pressure transducer connected to a guide catheter locatedin a patient's aorta, at the location of the ostium of the coronaryartery. The latter is standard procedure during a vascular intervention.The venous pressure P_(v) is known to be very low, on the order of a fewmm/Hg. In many, or even most, cases the venous pressure P_(v) can beneglected, i.e. be set to zero in the equations above. To actuallymeasure the venous pressure is, however, a relatively simple procedurewhich is accomplished through the insertion of a multipurpose catheterin the right atrium of the patient's heart.

The wedge pressure P_(w) deserves some attention. By definition, thewedge pressure P_(w) is the pressure distally of a stenosis when thestenosis totally occludes the artery. As can be seen in FIG. 2, themyocardium is then perfused only through the collaterals. To measure thewedge pressure requires therefore that total occlusion is produced inthe coronary artery. This can quite easily be artificially accomplishedthrough the inflation of a balloon attached to a balloon catheter, whichis introduced via a guide catheter. In a normal, healthy coronaryartery, the coronary artery is, however, by itself capable of supplyingthe myocardium with enough blood, and no collaterals are developed. Itshould therefore be clear that for a normal artery, the distal coronarypressure P_(d) is close to the aortic pressure P_(a), and it followsconsequently from Eqs. (5) and (6) that for an insignificant stenosisthe coronary fractional flow reserve FFR_(cor) is equal, or almostequal, to the myocardial fractional flow reserve FFR_(myo); andFFR_(myo) can therefore be substituted for FFR_(cor) in Eq. (3) tocalculate the normal maximum coronary flow Q_(s) ^(N), which is equal tothe normal maximum myocardial flow Q^(N). In short, for an insignificantstenosis, the extra step of creating total occlusion in an artery canoften be omitted. On the other hand, for a severe stenosis, a medicalintervention such as a PTCA must usually be undertaken, and suchoperation involves the creation of total occlusion and the wedgepressure can then simultaneously be measured without any extra efforts.When the relevant perfusion pressures have been measured and therelevant flows have been measured or calculated, different flowresistances can further be calculated through application of Eqs. (8),(9) and (10).

The method according to the present invention can now be summarized. Themethod comprises at least the steps of: (1) positioning a temperaturesensor mounted at a distal portion of a guide wire or other member at adistal position in a coronary artery of a patient, (2) positioning aninfusion catheter in the coronary artery such that the distal end of theinfusion catheter is located proximally (upstream) of the temperaturesensor, (3) measuring the blood temperature by the temperature sensor,(4) infusing a cold indicator fluid with a known infusion rate and knownor measurable temperature into the coronary artery by the infusioncatheter, (5) measuring the temperature of the mixture of blood andindicator fluid by the temperature sensor, and (6) calculating thecoronary blood flow by an equation based on the known and measuredquantities.

Preferably, the method comprises also the step of measuring thetemperature of the indicator fluid, which is conveniently andadvantageously done by retracting the sensor guide wire into theinfusion catheter until the temperature sensor is located inside theinfusion catheter and in the vicinity of the outlet opening of theinfusion catheter. Usually the method also comprises the step ofinducting steady state hyperaemia in the patient before the temperaturemeasurements are done, such that the calculated blood flow is themaximum coronary blood flow, which is the clinically most relevant typeof coronary blood flow. In practise, the method will often start withthe introduction of a guide catheter into the aorta of the patient, andthe infusion catheter and the sensor guide is then introduced via thisguide catheter.

When the calculated coronary blood flow is to be related to other flows,such as myocardial or collateral flows, or is to be related to normalflow values for this particular patient, or when different flowresistances are to be calculated, the above method can be supplementedwith further steps. The extended version of the method according toembodiments of the invention comprises at least the steps of: (1)positioning a temperature embodiments of sensor mounted at a distalportion of a guide wire at a distal position in a coronary artery of apatient, (2) positioning an infusion catheter in the coronary arterysuch that the distal end of the infusion catheter is located proximally(upstream) of the temperature sensor, (3) inducing steady statehyperaemia in the patient, (4) measuring the blood temperature by thetemperature sensor, (5) infusing a cold indicator fluid with a knowninfusion rate and a known or measurable temperature into the coronaryartery by the infusion catheter, (6) measuring the temperature of themixture of blood and indicator fluid by the temperature sensor, (7)calculating the maximum coronary blood flow by an equation based on theknown and measured quantities, (8) positioning a pressure sensor mountedat a distal portion of a guide wire at a distal position in the coronaryartery, (9) measuring a distal pressure by the pressure sensor, (10)measuring the aortic pressure, (11) calculating a first fractional flowreserve (FFR) value based on the measured aortic and distal pressures,and (12) calculating a related flow value, or a related FFR value, basedon the calculated maximum coronary flow and the first FFR value, or arelated flow resistance based on the measured pressures and a calculatedflow value.

Like before, the temperature of the indicator fluid is preferablymeasured with the temperature sensitive sensor, and in a preferredembodiment this sensor is also used for the pressure measurements, i.e.the sensor is a temperature sensitive as well as pressure sensitivesensor. It is, however, within the scope of the invention to use oneguide wire mounted sensor for the pressure measurements and anotherguide wire mounted sensor for the temperature measurements. The aorticpressure can be measured with the guide wire mounted pressure sensor,but is most conveniently measured with a separate pressure transducer influid communication with a guide catheter which has been inserted intothe patient's aorta, as is customary in cardiology practice. The methodabove can further be supplemented with a separate measurement of thevenous pressure, which can be accomplished by a multipurpose catheter,which is introduced into the right atrium of the patient's heart andwhich is in fluid communication with a pressure transducer. In manycases, the venous pressure can, however, be neglected, i.e. set to zero,in the different calculations. The calculation of some FFR valuesrequires knowledge of the so-called wedge pressure, which, bydefinition, can only be obtained at total occlusion of the coronaryartery. Total occlusion can be artificially induced by inflating aballoon provided at a balloon catheter introduced into the coronaryartery, for example via the above-mentioned guide catheter. The methodabove can therefore be supplemented with the steps of inducing totalocclusion and measuring the wedge pressure. In many cases, e.g. for aninsignificant stenosis, the distal coronary pressure is equal, or almostequal, to the aortic pressure, and the wedge pressure can be neglectedin the different calculations.

Besides the method described above, preferred embodiments of the presentinvention also provide a system for carrying out the method. Such asystem comprises an infusion catheter adapted to be introduced into acoronary artery, a guide wire having a distal portion provided with atemperature sensitive sensor and being adapted for insertion into acoronary artery, a device for transforming the output signals from thetemperature sensor into a temperature of the medium surrounding thesensor, and a device which is adapted to be connected to the infusioncatheter for continuously delivering a cold indicator fluid into thecoronary artery. The system can further be supplemented with a guidecatheter adapted to be introduced into the aorta of a patient.

When the system is utilized for carrying out the extended version of themethod, in which FFR values are to be obtained, the system comprisesfurther a pressure sensitive sensor mounted at a distal portion of aguide wire. This pressure sensor is in a preferred embodiment, the samesensor as is used for the temperature measurements. The system canfurther be supplemented with a pressure transducer adapted to beconnected to the guide catheter for measuring the aortic pressure. Inanother embodiment, the system also comprises a multipurpose catheteradapted to be inserted into the right atrium of a patient and adapted tobe connected to a pressure transducer for measurement of the venouspressure.

Although the present invention has been described with reference tospecific embodiments, also shown in the appended drawings, it will beapparent for those skilled in the art that many variations andmodifications can be done within the scope of the invention as describedin the specification and defined with reference to the claims below. Itshould in particular be noted that the skilled person would recognizethat the relative order of some of the steps in the method can bechanged without affecting the outcome of the method. Also, differentways of positioning the different instruments, e.g. the sensor guidewire and the infusion and guide catheters, at their respective positionscan be employed without departing from the scope of the invention. Asdiscussed above, blood temperature is preferably measured with the sametemperature sensor that is used for measurement of the mixturetemperature, but it is conceivable to use a separate sensor for theblood temperature measurement, especially if this extra sensor and theguide wire mounted temperature sensor are calibrated to each other. Aseparate temperature sensor would, for example, allow continuousmeasurement of the blood temperature during the whole thermodilutionprocedure.

1. A method for determining the blood flow in an individual coronaryartery of a patient, comprising at least the following steps:positioning a temperature sensor mounted at a distal portion of a guidewire at a distal position in the coronary artery; positioning aninfusion catheter in the coronary artery such that the distal end of theinfusion catheter is proximally of the temperature sensor; measuringblood temperature; infusing cold indicator fluid with a known infusionrate and known or measurable temperature into the coronary artery usingthe infusion catheter; measuring the temperature of the mixture of bloodand indicator fluid using the temperature sensor; and calculating thecoronary blood flow by a formula based on the known and measuredquantities.
 2. The method according to claim 1, further comprising thestep of retracting the temperature sensor until the temperature sensoris located inside the infusion catheter and measuring the indicatorfluid temperature at the end of the infusion catheter.
 3. The methodaccording to claim 1, further comprising the step of inducing steadystate hyperaemia in the patient before temperature measurement such thatthe calculated coronary blood flow is the maximum coronary blood flow.4. The method according to claim 3, wherein the formula used forcalculating the coronary blood flow is:$Q_{b} = {Q_{k}\frac{T_{k} - T_{b}}{T - T_{b}}}$ where Q_(b) is thecoronary blood flow, Q_(k) is the infusion rate of the indicator fluid,T_(k) is the temperature of the indicator fluid, T_(b) is bloodtemperature, and T is the temperature of the mixture of blood andindicator fluid.
 5. The method according to claim 1, wherein the formulaused for calculating the coronary blood flow is:$Q_{b} = {Q_{k}\frac{T - T_{k}}{T_{b} - T}}$ where Q_(b) is the coronaryblood flow, Q_(k) is the infusion rate of the indicator fluid, T_(k) isthe temperature of the indicator fluid, T_(b) is blood temperature, andT is the temperature of the mixture of blood and indicator fluid.
 6. Amethod for determining the blood flow in an individual coronary arteryof a patient and for relating this blood flow to at least one relatedflow value or to at least one related FFR value, comprising at least thefollowing steps: positioning a temperature sensor mounted at a distalportion of a guide wire at a distal position in the coronary artery;positioning an infusion catheter in the coronary artery such that thedistal end of the infusion catheter is proximally of the temperaturesensor; inducing steady state hyperaemia in the patient; measuring theblood temperature with the temperature sensor; infusing cold indicatorfluid with a known infusion rate and known or measurable temperatureinto the coronary artery using the infusion catheter; measuring thetemperature of the mixture of blood and indicator fluid using thetemperature sensor; calculating the maximum coronary blood flow by aformula based on the known and measured quantities; positioning apressure sensor mounted at a distal portion of a guide wire at a distalposition in the coronary artery; measuring a distal pressure by thepressure sensor; measuring the aortic pressure; calculating a first FFRvalue based on the measured aortic and distal pressures; and calculatinga related flow value, or a related FFR value, based on the calculatedmaximum coronary blood flow and the first FFR value, or a related flowresistance based on the measured pressures and a calculated flow value7. The method according to claim 6, further comprising the step ofretracting the temperature sensor until the temperature sensor islocated inside the infusion catheter and measuring the indicator fluidtemperature at the end of the infusion catheter.
 8. The method accordingto claim 6, wherein the temperature measurements and the measurement ofthe distal pressure are executed with the same guide wire mountedsensor.
 9. The method according to claim 6, wherein the temperaturemeasurements, the measurement of the distal pressure, and themeasurement of the aortic pressure are executed with the same guide wiremounted sensor.
 10. The method according to claim 6, wherein themeasurement of the aortic pressure is executed with a pressuretransducer connected to a guide catheter inserted into the patient'saorta.
 11. The method according to claim 6, further comprising the stepof inserting a catheter into the right atrium of the patient's heart andmeasuring the venous pressure by a pressure transducer connected to thecatheter.
 12. The method according to claim 6, further comprising thestep of positioning a balloon arranged at a catheter to a positionproximally of the pressure sensor, inflating the balloon to completelyocclude the coronary artery, and measuring the coronary wedge pressureusing the pressure sensor.
 13. The method according to claim 1, furthercomprising the step of measuring the blood temperature with thetemperature sensor.
 14. The method according to claim 1, wherein theinfusing comprises continuous infusing.
 15. A system for determining theblood flow in an individual coronary artery of a patient, comprising: asensor guide wire having a distal portion provided with a temperaturesensor and being adapted for positioning in the individual coronaryartery; an infusion catheter adapted for positioning in a coronaryartery and adapted for injecting an indicator fluid into the individualcoronary artery; a device for transforming an output signal from thetemperature sensor into a temperature of the medium surrounding thesensor; and a device adapted to be connected to the infusion catheterfor continuously delivering a cold indicator fluid from a reservoir intothe individual coronary artery.
 16. The system according to claim 15,further comprising a sensor guide wire having a distal portion providedwith a pressure sensor and being adapted for positioning in theindividual coronary artery.
 17. The system according to claim 16,wherein the pressure sensor and the temperature sensor are provided atthe same guide wire.